In the era of highly active antiretroviral therapy (HAART), the retinal manifestations of HIV infections have changed. The overarching goal of this grant is to apply the latest molecular biological, immunological, clinical study and drug development techniques to better understand these manifestations. The UCSD HIV study environment includes collaborations with several major NIH funded groups allowing fulfillment of these goals. CMV retinitis remains a problem, particularly in patients without access to or who fail HAART; especially the under represented minority community. We plan to determine which individuals are at immunological risk for CMV retinitis and to study a new manifestation of CMV retinitis immune recovery uveitis by analyzing ocular fluids and tissue from such patients for the presence of cytokines and CMV replication using molecular methods. In addition we will evaluate the role of anti-CMV therapy in the treatment of immune recovery uveitis in a UCSD IRB-approved randomized clinical trial. The non-infectious retinopathy of HIV, retinal cotton wool spots and microvascular disease, is still poorly understood. We wish to determine the molecular pathology and clinical correlates and relationship of HAART therapy to this disorder which is reponsible for focal retinal destruction and probably for visual dysfunction as well. We will do this by analyzing autopsy tissue obtained from the NIH funded California NeuroAIDS Tissue Network and from our own patient population. In addition, we will study the relationship of this retinopathy to neurocognitive dysfunction by studying a cohort of patients jointly enrolled in the NIMH funded UCSD HIV neurobehavioral research center. Our third aim is to develop a novel long acting intravitreal drug delivery system that can be administered as a small injection in the clinic. This is important because resistant CMV retinitis is still a problem in patients who have failed HAART therapy. At the current time, anti-CMV therapies, particularly intravitreal therapies, are not being aggressively pursued by pharmaceutical companies. We will synthesize and characterie new antiviral lipid conjugated drugs that are derivatives of ganciclovir and foscarnet. The anti-CMV activity of these compounds will be tested in vitro and long acting lipid derivatives will be produced and then tested in laboratory animals. The intravitreal therapeutic index and pharmacodynamics will be determined and efficacy studied in retinitis models. This will allow development of a low cost injectable drug delivery system that will allow treatment of resistant retinitis at intervals of every 3 months or longer without the added cost and risk of surgery in the operating room.